Mechanisms for Generating the Autonomous cAMP-Dependent Protein Kinase Required for Long-Term Facilitation in Aplysia

Chain, Daniel G.; Casadio, Andrea; Schacher, Samuel; Hegde, Ashok N.; Valbrun, Mireille; Yamamoto, Naoki; Goldberg, Alfred L.; Bartsch, Dušan; Kandel, Eric R.; Schwartz, James H.

doi:10.1016/s0896-6273(00)80686-8

Cited by 171 publications

(151 citation statements)

References 64 publications

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“…Only the dissociated catalytic subunits are active and capable of activating CREB by phosphorylating it at Ser-133. cAMP also regulates the proteosomal degradation of the regulatory subunits of PKA (13). To determine whether the loss of PKA activity in response to A␤ treatment was due to a failure to degrade the regulatory subunit, we examined the levels of isoform II␣ of the PKA regulatory subunit, the predominant neuronal isoform, as a function of exposure to A␤ .…”

Section: Resultsmentioning

confidence: 99%

Amyloid β-peptide inhibition of the PKA/CREB pathway and long-term potentiation: Reversibility by drugs that enhance cAMP signaling

Vitolo

Sant’Angelo

Costanzo

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

491

422

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Changes in hippocampal function seem critical for cognitive impairment in Alzheimer's disease (AD). Although there is eventual loss of synapses in both AD and animal models of AD, deficits in spatial memory and inhibition of long-term potentiation (LTP) precede morphological alterations in the models, suggesting earlier biochemical changes in the disease. In the studies reported here we demonstrate that amyloid ␤-peptide (A␤) treatment of cultured hippocampal neurons leads to the inactivation of protein kinase A (PKA) and persistence of its regulatory subunit PKAII␣. Consistent with this, CREB phosphorylation in response to glutamate is decreased, and the decrease is reversed by rolipram, a phosphodiesterase inhibitor that raises cAMP and leads to the dissociation of the PKA catalytic and regulatory subunits. It is likely that a similar mechanism underlies 〈␤ inhibition of LTP, because rolipram and forskolin, agents that enhance the cAMP-signaling pathway, can reverse this inhibition. This reversal is blocked by H89, an inhibitor of PKA. These observations suggest that 〈␤ acts directly on the pathways involved in the formation of late LTP and agents that enhance the cAMP͞PKA͞CREB-signaling pathway have potential for the treatment of AD. A lzheimer's disease (AD) is a progressive neurodegenerative disorder that is characterized by mild cognitive impairment at its onset and deficits in multiple cortical functions in later stages. To date, the vast majority of its symptoms have been attributed to the loss of synapses and the death of neurons that occur in the course of the disease. The overproduction and accumulation of the amyloid ␤-peptide (A␤) and particularly its 42-aa form (A␤ 1-42 ) have been shown to play a crucial role in both of these processes in animal models of AD (1, 2). Although these phenomena can account for the late debilitating stages of the disease, the mechanisms by which A␤ causes early cognitive and behavioral changes remain a matter of conjecture. Recent studies on animal models of AD have highlighted the discrepancy between behavioral deficits and neuropathological findings. Electrophysiological studies on mice that overexpress A␤ show impairment of long-term potentiation (LTP) that does not correlate with the extent of synaptic loss, amyloid deposition, or cell death (3-5). In addition, animals without detectable accumulation of A␤ have been reported to have behavioral deficits (6, 7). While examining gene expression in nerve growth factorprimed PC12 cells that had been exposed to A␤ 1-42 for 3 h, we observed that a group of genes including CREB2 (ATF4) and ubiquitin C-terminal hydrolase, which have been implicated in the switch from early to late LTP, were regulated in a manner consistent with an 〈␤-mediated inhibition of the cAMPmediated signaling pathway for the consolidation of LTP. ʈ The details of the biochemical pathway mediating the switch from early to late LTP have been worked out in aplysia and mice (8) and depend on the activation of the transcription factor CREB by phosphorylat...

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Section: Resultsmentioning

confidence: 99%

Amyloid β-peptide inhibition of the PKA/CREB pathway and long-term potentiation: Reversibility by drugs that enhance cAMP signaling

Vitolo

Sant’Angelo

Costanzo

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

491

422

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“…When degradation of an inhibitory protein is necessary for memory consolidation, proteasome inhibitors blocked the formation of longterm memory (Chain et al, 1999;Lopez-Salon et al, 2001;Upadhya et al, 2004). Conversely, when UPS functioned as an inhibitory constraint, removal of constraint by proteasome inhibitor enhanced synaptic transmission and facilitated memory formation (Zhao et al, 2003;Yeh et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Augmentation of Fear Extinction by D-Cycloserine is Blocked by Proteasome Inhibitors

Mao

Lin

Gean

2008

Neuropsychopharmacol

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D-Cycloserine (DCS) has been shown to facilitate extinction of conditioned fear in rats and to improve fear reduction of social phobia and fear of heights in human studies. Here, we investigate the mechanism of DCS effect by measuring internalized GluR1 and GluR2 using cell-surface biotinylation techniques. DCS selectively increased NMDA receptor-mediated synaptic response without affecting AMPA receptor-mediated synaptic response. Low-frequency stimulation (LFS) when applied in the presence of DCS induced GluR1 and GluR2 internalization in the amygdala slices. Proteasome inhibitors block DCS facilitation of LFS-induced depotentiation and a reduction in surface levels of GluR1 and GluR2. Furthermore, DCS in combination with LFS reduced cellular levels of PSD-95 and synapse-associated protein 97 (SAP97), which were also blocked by proteasome inhibitors. In the in vivo experiments, DCS-induced reduction of fearpotentiated startle and reversal of conditioning-induced increase in surface expression of GluR1 were blocked by proteasome inhibitors. DCS-treated rats fail to exhibit reinstatement after US-alone presentations. These results suggest that DCS facilitates receptor internalization in the presence of extinction training, resulting in augmented reduction of startle potentiation.

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“…Ap-uch was found to be critical for induction of LTF (Hegde et al 1997). Subsequently, Chain et al (1999) showed that at sensory-motor neuron synapses, injection of lactacystin, a specific proteasome inhibitor blocked induction of LTF. Since R subunits inhibit the activity of C subunits of PKA, the results suggested that the UPP operates to remove inhibitory constraints on the formation of long-term memory.…”

Section: The Upp and Long-term Synaptic Plasticitymentioning

confidence: 99%

“…The impetus for closely looking at the regulation of the neuronal proteasome came from conflicting results obtained with proteasome inhibitors on LTF in Aplysia. Originally, it was found that proteasome inhibitors block the induction of LTF (Chain et al 1999). Later studies on LTF, however, showed that bath application of the active form of lactacystin, clasto-lactacystin b-lactone, to sensory-motor neuron synapses resulted in enhanced LTF and an increase in neurite outgrowth in isolated sensory neuron (Zhao et al 2003).…”

Section: Does the Proteasome Have Local Roles In Synaptic Plasticity?mentioning

confidence: 99%

“…These studies failed to discover differential functions of proteasome in LTP because one study used MG-132 (Karpova et al 2006), which is not a highly specific proteasome inhibitor (Chain et al 1999;Tang and Leppla 1999), and the other used proteasome inhibitors lactacystin and epoxomycin at nanomolar concentration (Fonseca et al 2006), which is significantly lower than the effective concentration (micromolar) required to block proteasome activity.…”

Section: Does the Proteasome Have Local Roles In Synaptic Plasticity?mentioning

confidence: 99%

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The ubiquitin-proteasome pathway and synaptic plasticity

Hegde¹

2010

Learn. Mem.

129

123

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Proteolysis by the ubiquitin-proteasome pathway (UPP) has emerged as a new molecular mechanism that controls wideranging functions in the nervous system, including fine-tuning of synaptic connections during development and synaptic plasticity in the adult organism. In the UPP, attachment of a small protein, ubiquitin, tags the substrates for degradation by a multisubunit complex called the proteasome. Linkage of ubiquitin to protein substrates is highly specific and occurs through a series of well-orchestrated enzymatic steps. The UPP regulates neurotransmitter receptors, protein kinases, synaptic proteins, transcription factors, and other molecules critical for synaptic plasticity. Accumulating evidence indicates that the operation of the UPP in neurons is not homogeneous and is subject to tightly managed local regulation in different neuronal subcompartments. Investigations on both invertebrate and vertebrate model systems have revealed local roles for enzymes that attach ubiquitin to substrate proteins, as well as for enzymes that remove ubiquitin from substrates. The proteasome also has been shown to possess disparate functions in different parts of the neuron. Here I give a broad overview of the role of the UPP in synaptic plasticity and highlight the local roles and regulation of the proteolytic pathway in neurons.

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Mechanisms for Generating the Autonomous cAMP-Dependent Protein Kinase Required for Long-Term Facilitation in Aplysia

Cited by 171 publications

References 64 publications

Amyloid β-peptide inhibition of the PKA/CREB pathway and long-term potentiation: Reversibility by drugs that enhance cAMP signaling

Amyloid β-peptide inhibition of the PKA/CREB pathway and long-term potentiation: Reversibility by drugs that enhance cAMP signaling

Augmentation of Fear Extinction by D-Cycloserine is Blocked by Proteasome Inhibitors

The ubiquitin-proteasome pathway and synaptic plasticity

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